3,4-dihydro-benzo[e][1,3]oxazin-2-ones

The present invention relates 3,4-dihydro-benzo[e][1,3]oxazin-2-ones, e.g. which are mediators of human macrophage migration inhibitory factor (MIF) activity.

MIF is a cytokine with a wide variety of cellular and biological activities (see e.g. Orita at al., Curr. Pharm. Design 8:1297-1317, 2002; Nishihira, J Interferon Cytokine Res 20:751-762, 2000; Swope & Lolis, Rev. Physiol. Biochem. Pharmacol. 139:1-32, 1999; Metz & Bucala, Adv. Immunol. 66:197-223, 1997; and Bucala, FASEB J. 14:1607-1613, 1996). The three-dimensional crystal structure of human MIF reveals that the protein exists as a homotrimer (see e.g. Lolis et al., Proc. Ass. Am. Phys. 108:415-419, 1996).

MIF was found to inhibit the random migration of macrophages, and to be associated with delayed-type hypersensitivity reactions (see e.g. George & Vaughan, Proc. Soc. Exp. Biol. Med. 111:514-521, 1962; Weiser et al., J. Immunol. 126:1958-1962, 1981; Bloom & Bennett, Science, 153:80-82, 1966; David, Proc. Natl. Acad. Sci. USA 56:72-77, 1966). MIF was also shown to enhance macrophage adherence, phagocytosis and tumoricidal activity (see e.g. Nathan et al., J. Exp. Med. 137:275-288, 1973; Nathan et al., J. Exp. Med. 133:1356-1376, 1971; Churchill et al., J. Immunol. 115:781-785, 1975).

Recombinant human MIF was originally cloned from a human T cell library (see e.g. Weiser et al., Proc. Natl. Acad. Sci. USA 86: 7522-7526, 1989), and was shown to activate blood-derived macrophages to kill intracellular parasites and tumor cells in vitro, to stimulate IL-1β and TNFα expression, and to induce nitric oxide synthesis (see e.g. Weiser et al., J. Immunol. 147:2006-2011, 1991; Pozzi et al., Cellular Immunol. 145:372-379, 1992; Weiser et al., Proc. Natl. Acad. Sci. USA 89:8049-8052, 1992; Cunha et al., J. Immunol. 150:1908-1912, 1993).

More recently it has been found that MIF is not only a cytokine product of the immune system, but also is a hormone-like product of the endocrine system, particularly the pituitary gland. This work has underscored the potent activity of MIF as a counter-regulator of the anti-inflammatory effects of the glucocorticoids (both those endogenously released and those therapeutically administered), with the effect that the normal activities of glucocorticoids to limit and suppress the severity of inflammatory responses are inhibited by MIF and the endogenous MIF response may thus seen as a cause or an exacerbative factor in a variety of inflammatory diseases and conditions (see e.g. Donnelly and Bucala, Molecular Medicine Today 3:502-507, 1997).

MIF is now known to have several biological functions beyond its association with delayed-type hypersensitivity reactions. For example, MIF released by macrophages and T cells acts as a pituitary mediator in response to physiological concentrations of glucocorticoids (see e.g. Bucala, FASEB J. 14:1607-1613, 1996). This leads to an overriding effect of glucocorticoid immunosuppressive activity through alterations in TNF-α, IL-β, IL-6, and IL-8 levels. Additional biological activities include the regulation of stimulated T cells (see e.g. Bacher et al., Proc. Natl. Acad. Sci. USA 93:7849-7854, 1996), the control of IgE synthesis (see e.g. Mikayama et al., Proc. Natl. Acad. Sci. USA 90:10056-60, 1993), the functional inactivation of the p53 tumor suppressor protein (see e.g. Hudson et al., J. Exp. Med. 190:1375-1382, 1999), the regulation of glucose and carbohydrate metabolism (see e.g. Sakaue et al., Mol. Med. 5:361-371, 1999), and the regulation of tumor cell growth and of angiogenesis (see e.g. Chesney et al., Mol Med. 5:181-191, 1999; Shimizu et al., Biochem. Biophys. Res. Commun. 264:751-758, 1999; Mitchell & Bucala, Cancer Biol. 10:359-366, 2000). A role of MIF in atherogenesis (see e.g. Lin et al., Circulation Res. 8:1202-1208, 2000), in asthma (see e.g. Yamaguchi et al., Clin. Exp. Allergy 30:1244-1249, 2000), and in malaria (see e.g. Martiney et al., Infection Immunity 68:2259-2267, 2000) has also been implicated.

Anti-MIF antibodies have been shown to be active in a variety of models: endotoxin- and exotoxin-induced toxic shock (see e.g. Bernhagen et al., Nature, 365:756-759, 1993; Kobayashi et al., Hepatology, 29:1752-1759, 1999; Calandra et al., Proc. Natl. Acad. Sci. USA., 95:11383-11388, 1998; Makita et al., Am. J. Respir. Crit. Care Med. 158:573-579, 1998, Calandra et al., Nat. Med. 6:164-170, 2000), T-cell activation (see e.g. Bacher et al., Proc. Natl. Acad. Sci. USA. 93:7849-7854, 1996), autoimmune diseases, including rheumatoid arthritis (see e.g. Leech et al., Arthritis Rheum., 42:1601-1608, 1999), uveoretinitis (see e.g. Kitaichi et al., Curr. Eye Res., 20:109-114, 2000), glomerulonephritis (see e.g. Yang et al. Mol. Med. 4: 413-424, 1998), colitis (see e.g. de Jong et al., Nat. Immunol. 2:1061-1066, 2001; Ohkawara et al., Gastroenterol. 123: 256-270, 2002), multiple sclerosis (see e.g. Denkinger et al., J Immunol. 170:1274-82, 2003), atherosclerosis (see e.g. Burger-Kentischer et al. Atherosclerosis. 184:28-38, 2006) and skin graft destruction (see e.g. Hou et al., Transplantation 72: 1890-1897, 2001). Furthermore, anti-MIF antibodies have been shown to inhibit tumor growth and angiogenesis (see e.g. Chesney et al., Mol. Med. 5:181-191, 1999; Ogawa et al., Cytokine 12:309-314, 2000; Mitchell & Bucala, Cancer Biol. 10:359-366, 2000). Based on the activity of the anti-MIF antibodies, the therapeutic potential of low molecular weight MIF-inhibitors is high.

MIF shares significant sequence homology (36% identity) with D-dopachrome tautomerase, and has enzymatic activity to catalyze the tautomerization of the non-physiological substrates D-dopachrome (see e.g. Rosengren et al., Mol. Med. 2:143-149, 1996) and L-dopachrome methyl ester (see e.g. Bendrat et al., Biochemistry, 36:15356-15362, 1997) (FIG. 1A). Additionally, phenylpyruvic acid and p-hydroxyphenylpyruvic acid (see e.g. Rosengren et al., FEBS Letter, 417:85-88, 1997), and 3,4-dihydroxyphenylaminechrome and norepinephrinechrome (see e.g. Matsunaga et al., J. Biol. Chem., 274:3268-3271, 1999) are MIF substrates. Various inhibitors of the MIF tautomerase activity have been described (see e.g. Orita et al. J. Med. Chem. 44:540-547, 2001; Senter et al., Proc. Natl. Acad. Sci (USA) 99:144-149, 2002; Dios et al., J. Med. Chem. 45: 2410-2416, 2002).

It was now surprisingly found that a certain class of compounds is mediating MIF-activity, e.g. inhibiting MIF activity by inhibition of the tautomerase activity of MIF.

In one aspect the present invention provides a compound of formula

wherein R is hydrogen, or one or more, e.g. one, hydroxy, mercapto, SR₃, OR₃, or halogen,
R₁ is an aliphatic or arylic, optionally heterocyclic, group comprising in case of a non-heterocyclic group at least 6, e.g. 6 to 24 carbon atoms, and comprising in case of a heterocyclic group at least 6 ring members, e.g. 6 to 24,
e.g. wherein the heterocyclic group includes a fused heterocyclic ring (system), e.g. a ring (system) wherein another ring is anellated to heterocyclyl, and comprising 1 to 6 heteroatoms selected from N, O, S;
e.g. R₁ is preferably an aliphatic or arylic group comprising 6 to 24 carbon atoms and comprising a cyclic group,
e.g. including

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